Process for the preparation of DL-phenylglycine esters

ABSTRACT

A process for the resolution of DL-phenylglycine esters in which said ester is treated with (+)-tartaric acid in the presence of a mixture of solvents of different polarities, one of which is an alkanol having 1-4 carbon atoms, and the (+)-hermitartrate of the D-phenylglycine ester is selectively crystallised therefrom. Dphenylglycine and/or its salts may be obtained by hydrolysis of the ester thus formed. D-phenylglycine is a valuable intermediate in the synthesis of antibiotics of the penicillin and cephalosporin types. The present invention provides a relatively cheap, high yield process for the production of optically active esters of phenylglycine by way of their diastereoisomeric salts and for the production of optically active phenylglycine therefrom. Novel D-phenylglycine esters and salts are disclosed.

United States Patent [191 Phillipps et al.

[ June 3,1975

[ PROCESS FOR THE PREPARATION OF DL-PHENYLGLYCINE ESTERS [75] Inventors:Gordon Hanley Phillipps, Wembley;

7 Leslie Stephenson, Hanwell; Albert Roy Cooksey, Torver; John ColinClark, Gerrards Cross, all of England [73] Assignee: Glaxo LaboratoriesLimited,

Greenford, Middlesex, England 22 Filed: June 2,1972

21 Appl. No.: 259,298

[30] Foreign Application Priority Data 6/1956 Vercellone et a1. 260/471A Primary ExaminerLorriane A. Weinberger Assistant ExaminerL. A.Thaxton, Attorney, Agent, or Firm-Bacon & Thomas [5 7] ABSTRACT Aprocess for the resolution of DL-phenylglycine esters in which saidester is treated with (+)-tartaric acid in the presence of a mixture ,ofsolvents of different polarities, one of which is an alkanol having 1-4carbon atoms, and the (+)-hermitartrate of the D- phenylglycine ester isselectively crystallised therefrom. D-phenylglycine and/or its salts maybe obtained by hydrolysis of the ester thus formed.

D-phenylglycine is a valuable intermediate in the synthesis ofantibiotics of the penicillin and cephalosporin types. The presentinvention provides a relatively cheap, high yield process for theproduction of optically active esters of phenylglycine by way of theirdiastereoisomeric salts and for the production of optically activephenylglycine therefrom. Novel D-phenylglycine esters and salts aredisclosed.

18 Claims, No Drawings PROCESS FOR THE PREPARATION OF DL-PHENYLGLYCINEESTERS The present invention relates to a novel process for theproduction of optically active esters of phenylglycine by way of theirdiastereoisomeric salts and to the production of optically activephenylglycine therefrom.

In the pharmaceutical industry, D-phenylglycine(D-2-amino-2-phenylacetic acid) is a valuable intermediate in thesynthesis of antibiotics, e.g. 6B-(D-2- amino-2-phenylacetamido)penicillanic acid.(ampicillin), 7B-(D-2-amino-2-phenylacetamido)-3-methylceph-3-em-4-carboxylic acid (cephalexin), 3-acetoxymethyl-7B-(D-Z-amino-2-phenylacetamido) ceph-3-em-4-carboxylicacid (cephaloglycin), 7B-[D- 2-amino-2-(1,4-cyclohexadien-l-yl)-acetamido]-3- methylceph-3-em-4-carboxylic acid, and 6B-[D-2-amino-2-(p-hydroxyphenyl)acetamido] penicillanic acid (amoxycillin) andothers.

A commercial method used at present for resolving the zwitterionicDL-2-amino-2-phenylacetic acid requires the use of a strong opticallyactive acid to form a salt of both D-and L-enantiomers, and relies uponthe difference in solubility found in such salts in order to effect aseparation of the D- and L-enantiomers. The acid most favoured forcarrying out this separation on a production scale is the expensive(+)-l0-camphorsulphonic acid which is prepared from natural camphor bysulphonation. The economics of processes employing(+)-l0-camphorsulphonic acid are thus markedly dependent on efficientrecovery of this acid, a process which proves plant and labourintensive, and therefore costly, in practice on a commercial scale.

Whilst the resolution of N-acyl DL-2-amino-2- phenylacetic acid has beendescribed by several workers (Fischer & Weichhold, Ber. 1908, 31 1286;Lutz, Ber., 1932, 65 1609; Potapov et al., Chem. Abstr. 1966, 65 7029;Minovici, Bull soc. chim. Romania, 1920, 2, 8 see Chem. Abstr. 1920, 14,3228; Gottstein and Cheney J.Org.Chem., 1965, 30, 2072) the opticallyactive bases employed are generally expensive. Added to this expense thehigh molecular weight of the optically active bases is such that largequantities are required for stoichiometric salt formation wtih the N-acylate. Furthermore, hydrolysis of the optically active acylates of the2-amino-2-phenylacetic acid produced by such resolution processesusually results in some undesirable racemization leading to opticallyimpure 2-amino-2-phenylacetic acid.

ln order to avoid using strong optically active acids, it has beenproposed to resolve the DL-phenylglycine in the form of an ester, thusenabling cheap readily available optically active carboxylic acids to beused. However, it has not previously proved possible to effect a singlestage crystallisation giving the desired product in acceptable yield andof acceptable optical purity. Losse et al. (Chem. Ber. 1958, 91, 2410)have described a resolution of ethyl DL-phenylglycinate with dibenzoylL(+)-tartaric acid in which the initial crystallisation was inefficientand fractional crystallisation of the salts was required. However,dibenzoyl L(+)- tartaric acid offers little economic advantage over(+)-l0-camphorsulphonic acid and a multi-stage fractionation process forthe separation of the optical enantiomers makes considerable demands onboth plant and labour and is thus not an attractive commercialproposition. Losse et al. further found that in their hands hydrolysisof the resolved ethyl ester led to loss of optical purity owing topartial racemisation during the hydrolysis, suggesting that resolutionof esters of phenylglycine was not commercially worthwhile.

In our copending patent US. application Ser. No. 221,810 we have shownthat esters of DL- phenylglycine may be obtained readily in good yieldsfrom 2-phenylacetic esters, some of which are available in largequantities as waste by-products from the production of semi-syntheticpenicillin and cephalosporin antibiotics. It is thus highly desirablecommercially to be able to resolve these relatively cheap esters of DL-phenylglycine successfully and cheaply.

Surprisingly we have now found that it is possible by selecting theright conditions to resolve these readily available DL-esters using(-l-)-tartaric acid, which is very readily available, and to obtain thesalt of the desired D-phenylglycine ester in good yields in high opticalpurity, in a single crystallisation step, thus avoiding a time-consumingfractionation procedure. Furthermore, by using selected conditions it ispossible to convert the resolved esters in high yields into D-phenylglycine with little or no loss of optical purity, in contrast tothe previous finding of Losse.

In addition to this, the unwanted isomer in the mother liquors may besimply racemised and this mixture resolved and hydrolysed as before toachieve a high conversion of racemic ester into the optically activeisomer.

According to the present invention we provide a process for theresolution of a DL-phenylglycine ester of the formula:

where R represents an alkyl group with 1 to 6 carbon atoms or acycloalkyl group with 5 to 6 carbon atoms which comprises treating saidDL-phenylglycine ester of formula I with (+)-tartaric acid in thepresence of a mixture of solvents of different polarities one of whichis an alkanol having l-4 carbon atoms, and selectively crystallising the(+)-hemitartrate of the D- phenylglycine ester therefrom.

The (+)-hemitartrate salts of the esters of formula I in substantiallyoptically pure form are new compounds and constitute a further featureof the invention.

DL-phenylglycine esters of formula I are preferably used in which Rrepresents a methyl, ethyl, isopropyl, butyl, isobutyl or cyclohexylgroup.

We have found that although the ester hemitartrates can be partiallyresolved by crystallisation from a single solvent such as an alkanol, amore efficient resolution can be effected by using a mixed solvent,containing an alkanol together with a solvent having a significantlydifferent polarity. In general, there will be a predominant proportionof the alkanol.

While we do not wish to be bound by theoretical considerations, it isbelieved that the D-phenylglycine ester hemitartrate more readily formsa solvate with the alkanol solvent than does the L-isomer. lt is thissolvate which is normally crystallised initially, although the alkanolcan be removed by drying, methanol usually being more loosely bound thanethanol. The L-isomer is not normally recovered in the form of such asolvate.

In general, the solvent mixture will contain, in addition to thealkanol, a solvent selected from the following: water; sulphoxidesolvents such as dimethyl sulphoxide; amide solvents such as formamide,dimethyl formamide, dimethylacetamide and hexamethyl phosphoramide;nitrile solvents such as acetonitrile; ester solvents such as methyl andethyl acetate; carboxylic acids such as acetic and propionic acid;hydrocarbon solvents such as benzene and toluene; and chlorinatedhydrocarbon solvents such as methylene chloride or dichloroethane.

The solvent mixture preferably contains predominantly the alkanol,especially methanol or ethanol, or a mixture of such alkanols such asindustrial methylated spirit (l.M.S.).

In a preferred embodiment of the process, the solvent mixture comprisesan alkanol containing a small proportion e.g. l-20 percent, preferably-15 percent, v/v, of a more polar cosolvent advantageously a sulphoxidesolvent such as dimethyl sulphoxide; water; an amide solvent such asformamide, dimethyl formamide or hexamethyl phosphoramide; a nitrilesolvent such as acetonitrile; or an ester solvent such as methylacetate. Inclusion of these co-solvents has been found to increase thepurity of the product although lowering slightly the yield obtained.With inclusion of water, an optimum of about percent by volume providesgood yields of acceptable purity. Alternatively, a less polar solventmay be included, for example a hydrocarbon or a chlorinated hydrocarbonsuch as methylene chloride, dichloroethane or benzene; or a carboxylicacid such as acetic or propionic acid.

Although aqueous lower alkanols generally are suitable as solvents, andethanol containing dimethyl sulphoxide or acetic acid is also generallyuseful, it has been found particularly advantageous to use aqueousmethanol or aqueous ethanol in resolving ethyl DL- phenylglycinate andaqueous ethanol or aqueous l.M.S. in resolving methylDL-phenylglycinate.

The salt-forming reaction is preferably effected at ambient or slightlyelevated temperature, e.g. to 60C, or even under reflux, preferably 40to 50C, subsequently cooling to obtain crystallisation. In general, theupper and lower temperatures of crystallisation fall within the range to+60C, preferably 0 to 20C. It is particularly desirable to form the saltat temperatures between 20 and 60C, and then carefully to cool thereaction mixture at a controlled rate whereby steady crystallisation isobtained yielding a particularly pure product. Seeding the solution witha crystal of the desired pure D-salt is also beneficial.

The tartaric acid may be used in a stoichiometric amount or in excess,e.g. up to 100 percent excess. Optimal yields have been obtained usingfrom 1 to 1.75 moles of the acid.

The concentration of the unresolved phenylglycine ester in the solventmixture may in general be from 1 to 20 percent w/v, but this willobviously vary with the alkanol. With the inclusion of 10 percent water,we have found that preferred concentrations of the ester are formethanol about 15 percent w/v, for ethanol from 2 to 5 percent w/v andfor I.M.S. from 5 to 10 percent w/v.

In general, the smaller the quantity of co-solvent which is used, thelower the concentration of the phenylglycine ester starting material.

When resolving an ester prepared according to the process of our saidcopending application, it is convenient to add the tartaric aciddirectly to the crude filtrate from the final stage which is normallyhydrogenation. Where the hydrogenation solvent would be undesirable, thecrude mixture may be evaporated and the residue dissolved in the solventof choice.

The conversion of the salts of optically active 2-amino-2-phenylaceticacid esters into optically active 2-amino-2-phenylacetic acid may becarried out by first removing the (+)-tartaric acid, e.g. on a basic ionexchange column or by formation of an insoluble tartrate, e.g. byaddition ofa calcium salt, e.g. calcium chloride, or ammonia andhydrolysing the free optically active 2-amino-2-phenylacetic ester, e.g.in a boiling dilute solution of a strong acid. Alternatively the freeoptically active 2-amino-2-phenylacetic ester may be obtained byneutralising the optically active hemitartrate with a base, e.g. aqueousammonium hydroxide or sodium bicarbonate to ca. pH7 and extracting withan organic solvent. Care must be exercised in releasing the freeoptically active 2-amino-2-phenylacetic ester since the use of base inthis process can lead to racemisation of the optically active2-amino-2-phenylacetic ester ln addition the optically active2-amino-2-phenylacetic ester can itself racemise, especially on warming.

Because of the risk of racemisation we have found it advantageous simplyto hydrolyse the hemitartrate of the optically active2-amino-2-phenylacetic ester under acid conditions (i.e. one avoidsreleasing the free optically active amino ester). Alternatively thehemitartrate may be converted into another salt before hydrolysis. Whenthe process is operated in any of these ways no or very littleracemisation occurs, and 2-amino-2- phenylacetic acid of good opticalpurity can be obtained.

Thus according to a further feature of the present invention,D-phenylglycine may be obtained by'hydrolysing the obtained D-ester(+)hemitartrate in an aqueous solution of a strong acid, such as amineral acid or an alkaneor arylsulphonic acid or a halogenatedcarboxylic acid, e.g. hydrochloric, hydrobromic, hydriodic, sulphuric,phosphoric, perchloric, trifluoroacetic, methanesulphonic or p-toluenesulphonic acid.

The hydrolysis reaction may be carried out at l0 to +200C and isconveniently effected .at the boiling point of the aqueous acidsolution. It has been found that even at the boiling point little or noracemisation occurs.

The product of the hydrolysis is a solution containing a salt of theoptically active 2-amino-2-phenylacetic acid. The optically active2-amino-2-phenylacetic acid may be liberated by adjusting the pH of thehydrolysis mixture with a base to a pH in the range 4-9, preferably 6-7,and filtering.

Clearly to minimise the usage of base in the pH adjustment step theamount of acid is preferably reduced to a minimum. We have found thatvery concentrated slurries of optically active 2-amino-2-phenylaceticester salts can be converted into optically pure 2-amino-2-phenylaceticacid in very high yield, enabling considerable economies in reagentcosts to be made. 4

The (+)-tartaric acid may be recovered from the mother liquors byconventional techniques and recycled.

Further economies in process costs may be made by recovering theunwanted optical isomer from the mother liquors after filtering off theinsoluble salt of the desired optically active 2-amino-2-phenylaceticester and the (+)-tartaric acid. If desired, the (+)-tartaric acid canbe removed, c.g. on a basic resin column. The unwanted enantiomer maythen be raccmised by heating alone, or with a weak acid such as aceticacid or a base such as ammonia or an alkali metal alkoxide or hydroxide.Dry conditions are, however, preferably since the presence of water cancause hydrolysis thus necessitating the re-esterification of anyDL-2-amino-2- phenylacetic acid so formed. In many cases, it is thusmore convenient to racemise the (+)-hemitartrate of the L-enantiomer byheating in dry form or in solution e.g. in dry methanol or ethanol,advantageously in the presence of a slight excess of tartaric acid.Although in alcoholic solvents some trans-esterification may occur, thissimple racemisation step leads to a valuable yield of D-phenylglycineand thus renders the process even more commercially viable. The problemof hydrolysis during recovery of the other optical isomer when water ispresent in the medium, is avoided by an alternative embodiment of theresolution process mentioned above, namely the use as solvent of analcohol, e.g. methanol or ethanol, and a hydrocarbon or chlorinatedhydrocarbon, e.g. methylene chloride, dichloroethane or benzene; anamide e.g. formamide, dimethylformamide, hexametbyl phosphoramide;acetonitrilc; an ester, e.g. methyl acetate; a sulphoxide such asdimcthyl sulphoxide or a carboxylic acid such as acetic acid.

In general, strongly electron-donating solvents such as sulphoxides andacids favour racemisation and when these are used as co-solvents in theresolution process, the same solvent mixture can be used in theracemisation stage.

It has further been found that some racemisation occurs during theresolution process so that the yield of the desired D-isomer may then bemore than 100 percent based on the D-isomer initially present. Thepresence of strongly electron-donating solvents such as sulphoxides andacids has been found to accelerate this process. The racemisation israpid at 60C and is significant even at C. At such lower temperatures,the resolution should be allowed to continue for a prolonged period e.g.several days in order to obtain a useful level of racemisation. Thus,for example, using sulphoxide or acid co-solvents yields as high as 130percent have been observed.

Coupled with the process described in our above mentioned copendingapplication, the process of the present invention provides aparticularly convenient and economic route to D-phenylglycine fromesters of phenylacetic acid.

Thus in the combined process, a phenylacetic acid ester is reacted witha base and an organic nitrosating agent to yield a Z-nitrosatedphenylacetic ester. This nitrosated intermediate, without firstseparating the various reaction products which may be present, is thenreduced to afford the DL-phenylglycine ester which can then be resolvedaccording to the present invention, preferably without prior isolationand purification.

The phenylglycine ester starting materials may also be prepared bydirect esterification of DL- phenylglycine.

The following examples further illustrate the invention.

Samples of hemitartratcs which were dried at 70-80C at 2mm. wereunsolvated. Ethanol crystallisates dried at 20-40C and 2 mm. weresolvated usually with 1 mol. of ethanol. The yields and rotations ofethanol solvates have been corrected to allow for the solvation. Whenethanol solvates have been dried to drive off the solvent the productpicks up atmospheric water to give a hemihydrate; the yields androtations of such hemihydrates have not been corrected.

l.M.S. containing 10 percent water was made from l.M.S. which hadpreviously been dried and distilled. Ethanol containing 10 percent waterwas made from Burroughs Absolute ethanol. Melting points are uncorrectedand were measured on a Kofler block. Unless otherwise stated,temperatures are in C:

EXAMPLE l Resolution of Pure Methyl DL-phenylglycinate in Ethanol.

To a solution of (+)-tartaric acid (3.0g; 0.02 mole) in aqueous ethanolml) (EtOH: H O 90:10 v/v) kept at about 50C was added pure methyl DL-phenylglycinate (3.3g: 0.02 mole). The solution was allowed to cool to5C and to stand at this temperature for 16 hours. The hemitartratecrystals formed were filtered, washed with aqueous ethanol and driedunder vacuum at 40C to yield methyl D-phenylglycinate (+)-hemitartrate(3.0g; 83 percent) [01],, 63.0 (H O); m.p. 143l45C (with decomp) n.m.r.DMSO- d 5 protons 7.43 8 (C5H5) (Multiplet) 1 proton 5-03 8 (s) 2protons 4.15 5 (s) 3 protons 3.68 8 (methyl)(s) i.r. (nujol) 3460 cm."(SH) 3370 cm. (M) 1760 cm. "(5).

EXAMPLE 2 Resolution of Pure Ethyl DL-phenylglycinate in Methanol.

To a solution of (+)-tartaric acid (8.4g; 0.056 mole) in aqueousmethanol (65ml) (MeOH: H O 90:10 v/v) kept at about 60C was added pureethyl DL- phenylglycinate (10g: 0.056 mole) The solution was allowed tocool to 5C and kept at this temperature for 16 hours. The hemitartratecrystals were filtered off, washed with aqueous methanol (10ml) anddried under vacuum at 40C to give ethyl D-phenylglycinate(+)-hemitartrate (7.4g; 80.4 percent) [01],, -43 (H O); m.p.l23.5127.5C.

EXAMPLE 3 Resolution of Pure lsopropl DL-phenylglycinate in Ethanol.

To a solution of (+)-tartaric acid (3.87g: 0.026 mole) in aqueousethanol ml) (EtOH: H O 90:10 v/v) kept at about 60C, was added pureisopropyl DL- phenylglycinate (5.0g: 0.026 mole). The solution wasallowed to cool to 5C and kept at this temperature for 16 hours. Thehemitartrate crystals were filtered off, washed with aqueous ethanol anddried under vacuum at 40C to give isopropyl D-phenylglycinate(+)-hemitartrate (358g: 71.0 percent) [01],, -35 (H O); m.p. l49l50C. Asample redried to remove ethanol had m.p. 149-150C, v,,,,, (Nujol) 3320and 3272 (OH), 2730 (NH 1735 (CO CHMe 1572 (CO[) and 1670 cm (CO H), 1'(D CSOCD 2.56 (5H,s; Ph), 5.12 (lH,s,CHPh) 5.88 (2H,s; tartrate) 5.0(1H, septet, J6H CH of isopropyl) 8.72 (3H,d, J6H CH of isopropyl), 8.84(3H,d,.l6H ;other CH;, of isopropyl. magnetic non-equivalence) (Found:C, 51.15; H, 6.1;

N,3.8. C, H NO .O.5H O requires C,51.2; H, 6.3; N,4.0 percent).

EXAMPLE4 Resolution of Pure Methyl DL-phenylglycinate.

A solution of recrystallised methyl DL- phenylglycinate (383 mg: 2.32m.mole) in I.M.S. containing percent water (4 ml.) was filtered into awarm solution of (+)-tartaric acid (365mg: 2.42 m.mole, 1.04 equiv.) inthe same solvent (4 ml.). The homogeneous solution was seeded with anearlier sample of the D-hemitartrate (clusters of very small needles,[al -625). The product crystallised in an hour at was filtered and driedat 7012 mm for 16 hours to give small needles of the hemitartrate (236mg; 70 percent) m.p. l39141, [a],, 62.5 (C 1.04, H O), v (Nujol) 3475 to2640 [OH and NH 1740 and 1250 (CO Me) 1730 to 1650 (CO H), 1587 (CO and690 and 737 cm (Ph). 1- (D CSOCD 2.6 (5 proton singlet; Ph) 5.1 (1proton singlet; PhCH), 5.88 (2 proton singlet; [CHOH] 6.3 (3 protonsinglet; CO Me). (Found: C, 47.6; H, 5.25; N, 4.1, C H NO 0.5 H 0requires C, 47.85; H, 5.5; N, 4.3 percent).

EXAMPLE 5 Resolution of the Crude Reaction Mixture from theHydrogenation of the Oxime of Methyl Phenylacetate in Ethanol.

Half of the final filtered solution from the hydrogenation reactiondescribed in Example 1 of the Specification of U.S. application Ser. No.221,810 was evaporated under vacuum to leave an oily residue containingcrude esters of phenylglycine (approx. 3.8g: 0.024 mole) This residuewas added to a solution of (+)-tartaric acid (4.0g: 0.025 mole) inaqueous ethanol (100 ml) (EtOH: H O 90:10 v/v) at about 50C. The warmsolution was filtered and, when cool, seeded with methylD-phenylglycinate (+)-hemitartrate crystals and allowed to stand at 5Cfor 16 hours. The hemitartrate crystals were filtered off, washed withaqueous ethanol and dried under vacuum at 40C to yield methyl D-phenylglycinate (+)-hemitartrate (2.41g: 55.5 percent) [a] 60.5 (H O).

EXAMPLE 6 Resolution of the Crude Reaction Mixture from theHydrogenation of the Oxime of Methyl Phenylacetate Using Tartaric Acidin Ethanol.

To a final filtered solution in ethanol (45 mls) from a hydrogenationreaction (similar to that described in Example 5) containing crudeesters of phenylglycine (approx. 2.1g; 0.012 mole), was added(+)-tartaric acid (1.9g; 0.0125 mole) in water (5 ml) at about 50C. Thewarm solution was filtered and when cool seeded with methylD-phenylglycinate (+)-hemitartrate crystals and allowed to stand at 5for 16 hours. The hemitartrate crystals were filtered off, washed withaqueous ethanol and dried under vacuum at 40C to yield methylD-phenylglycinate(+)-hemitartrate (1.18g; 52 percent) [01],, 63.0. (H0).

EXAMPLE 7 Resolution of the Crude Reaction Mixture from theHydrogenation of the Oxime of Methyl Phenylacetate Using Tartaric Acidin I.M.S.

To the final filtered solution in I.M.S. (90 mls) from a hydrogenationreaction (similar to that described in Example 5) containing crudeesters of phenylglycine (approx. 4.18g; 0.024 mole), was added(+)-tartaric acid (3.8g; 0.025 mole) in water 10 ml) at about 50C. Thewarm solution was filtered and when cool seeded with methylD-phenylglycinate (+)-hemitartrate crystals and allowed to stand at 5for 16 hours. The hemitartrate crystals were filtered off, washed withaqueous I.M.S. and dried under vacuum at 40C to yield methylD-phenylglycinate (+)-hemitartrate (2.10g; 46.0 percent) [a],, 56 (H O).

EXAMPLE 8 Resolution of Ethyl DL-phenylglycinate with (+)-tartaric Acida. In ethanol containing 10 percent water A solution of ethylDL-phenylglycinate 1.057 g., 5.9 mmole) in ethanol containing 10 percentwater was warmed with (+)-tartaric acid (0.949 g., 6.3 mmole, 1.07equiv.) in the same solvent (total volume 10.5 ml.). The solution wascooled to 20 and was filtered after 16 hours and dried at to giveD-hemitartrate (634 mg., 66 percent) as needles, m.p. 131 to 135, [12146 (c 2.5, H 0), u (Nujol) 3452 and 3400 (OH), 2620 (NH and 1740 cm. (COEt), r (D CSOCD 2.71 (5H,s;Ph), 5.05 (1H,s;CHPh), 5.89 (2H,s;tartrate),5.82 (2H,q, J7Hz; CH of ethyl) and 8.88 (3H, t; J7Hz; CH of ethyl).(Found: C,49.25; H,5.65; N,4.l. C H NO .O.5H O requires C,49.75; H,5.95and N,4.15 percent).

b. In ethanol containing 20'percent water The ester was resolved using a20 percent solution in ethanol containing 20 percent water to give thehemitartrate (46 percent yield), [011 46 (c 2.51, H O).

EXAMPLE 9 Resolution of Methyl DL-phenylglycinate A solution of methylDL-phenylglycinate 19.827 g., 120 mmole, m.p. 3233, made byesterification of DL-phenylglycine with methanol/hydrogen chloride) inlMS containing 10 percent water was filtered into a warm solution of(+)-tartaric acid in the same solvent The total volume used was 290 ml.,giving a 7 percent solution of the ester. A seed (clusters of smallneedles, [01],, 62.5) was added to the warm solution and fine needleswere slowly deposited. After 3 hours cooling to 20, the thick mass wasrefrigerated at 3 for 15 hours, filtered, washed with chilled solventand dried at for 4 hours to give the hemitartrate (15.447 g., 82percent) as needles, m.p. l40l45, [02],, 59.5 0.912, water) and 60 (c0.936, water) w "m. (nujol) 3480, 3410 (OH), 1740 and 1250 (CO Me). 1730to 1650 (CO H), 1587 (COf), 737 cm" 1' (D 0) 2.45 (5-proton singlet;Ph), 4.66 (l-proton singlet; PhCH), 5.49 (2-proton singlet; [CHOH](3-proton singlet; CO- Me). (Found: C, 47.6; H, 5.2; N. 41. C H No 0.5 H0 requires C, 47.85; H. 5.55; N. 4.3 percent).

A Sample (2.046 g.) was recrystallised from hot ethanol containing 10percent water (20 ml.) to give needles [a],, -62 (c 0.982. water) and61.5(c 0.990,

water). Another sample (2.123 g.) was recrystallised from hot lMScontaining 10 percent water (20 ml.) to give needles [04],, 64.5 (c(1.98. water) and 64 (c 1.019, water).

The mother liquors from the resolution were cooled to give two crops(290 mg.) and (2.435 g.) with [01],, of +28.5 and +25.5 respectively.

EXAMPLE 10 Hydrolysis of Methyl D-phenylglycinate (+)-hemitartrateMethyl D-phenylglycinate (+)-hemitartrate 1.5g: 4.8 mmoles; from Example1 was dissolved in cold 6N hydrochloric acid ml) and the mixture wasthen boiled under reflux for 75 min. After cooling the pH was adjustedto 7.0 with ammonium hydroxide solution. The precipitate was collectedby filtration, washed with water and dried under vacuum at 38C to yieldD- phenylglycine (043g: 60 percent) [01],, -l56.8 ([N- HCl) mp 255 (withsublm.)

EXAMPLE 11 Hydrolysis at a Higher Concentration.

EXAMPLE 12 Hydrolysis With a Shorter Reflux Time.

Methyl D-phenylglycinate(+)-hemitartrate (prepared as in Example 1;0.39g: 1.2 mmole) was dissolved in cold oN-hydrochloric acid (4 ml.) andthe solution was boiled under reflux for mins. After cooling the pH wasadjusted to 7.0 with ammonium hydroxide solution. The precipitate wascollected by filtration, washed with water and dried under vacuum at38C. to yield D-phenylglycine (0.1 l6gz62 percent) [011 l52 (lN-HCl).

EXAMPLE l3 Hydrolysis of Methyl D-phenylglycinate(+)-hernitartrate byAdding to Boiling 6N-HC1.

Methyl D-phenylglycinate(+)-hemitartrate (prepared as in Example 1;2.0g: 6.3 mmole) was added portion-wise to boiling 6N-hydrochloric acid(15 ml.)

at such a rate as to keep the reaction mixture boiling.

After the addition was complete the mixture was boiled under reflux for1 hour. When cool the pH was adjusted to 7.0 with ammonium hydroxidesolution. The precipitate was collected by filtration. washed with waterand dried under vacuum at 38C. to yield D-phenylglycine (0.54g:55.5percent) [cvl -156. (1.0N HCl) EXAMPLE l4 Hydrolysis of lsopropylD-phcnylglycinate(+)-hemitartrate by Adding to Boiling N-HCl.

lsopropyl D-phenylglycinatet+)-hemitartratc (prcpared as in Example 3'.2.0g:5.8 ntmole was added portionwise to boiling oN-hydrochloric acid(15 ml.) at such a rate as to keep the reaction mixture boiling. Afterthe addition was complete the mixture was boiled under reflux for lhour. When cool the pH was adjusted to 7.0 with ammonium hydroxidesolution. The precipitate was collected by filtration. washed with waterand dried under vacuum at 38C. to yield D-phenylglycine (065g: 74percent) [a],,'-'" -l58.8. (1N HCl) EXAMPLE l5 Hydrolysis of EthylD-phenylglycinate-(+)hemitartrate.

A solution of ethyl D-phenylglycinate (+)-hemitartrate ([a],, 48.5, 620mg., 1.88 mmole) in 6N- hydrochloric acid l.26;ml.. 7.5 mmole). 4equiv.) was refluxed for 1 hour. Water (6 ml.) was added and the pH ofthe solution was adjusted to 7.0 with saturated sodium bicarbonatesolution (14.0 ml). D- phenylglycine (98 mg, 35 percent) wasprecipitated as plates 155 (c 0.965, 1N-HC1) identical to authenticmaterial.

EXAMPLE l6 D-Phenylglycine by Hydrolysis of Methyl D-phenylglycinateMethyl D-phenylglycinate (20.25 g., 122 mmole, [aln *l36) was added torefluxing 6N-hydroch1oric acid (86 ml.. 515 mmole, 4.2 equiv.) during 5minutes. The solution was refluxed (1 10) for 25 minutes. Water ml.) wasadded, cooling the solution to 50. Ammonium hydroxide solution (61 ml.of approx. 10 N, 610 mmole) was added to give a solution of pH 7.0 Asolid was precipitated beginning at pH 1.5. The suspension was cooled to0, filtered and washed with water to give pale yellow plates (13.08 g.,71 percent) D- phenylglyeine. The filtrate (250 ml.) had [01],, 1.12;the washings ml.) [04],, -0.50. 1f the rotation of the filtrates wassolely caused by phenylglycine with the same specific rotation as thesolid then a further 2.5 g. (13 percent) of phenylglycine was present.The solid had [01],, 154 (c 1.057,1 N-HCl) and 154 (c 1.001.1 N-HCl),and resembled an authentic sample of phenylglycine (i.r., n.m.r.).

EXAMPLE l7 D-Phenylglycine from Methyl D-phenylglycinate HydrochlorideMethyl D-phenylglycinate hydrochloride (23.6 g., 110 mmole). was addedto boiling oN-hydrochloric acid (47 m1., approx. 2.8 equivs.), keepingthe mixture boiling. The solution was refluxed for 30 minutes, thenwater (70 ml.) and 0.880 ammonia (35.5 ml.) were added to bring the pHto 7.0. The suspension was cooled to 0, filtered. washed and dried togive D- phenylglycine as plates (12.89 g., 74 percent) [01],, 157 (c0.998.1N-HC1). [01],, l56.5 (c 0.994. 1N- HCl). The filtrate (210 ml..a=1.47) and washings (56 ml.. 0z=0.54) containing a further 2.15 g. (12percent) if the rotation was solely caused by dissolved phenylglycinewith the same rotation as the precipit'tllctl solid.

EXAMPLE 18 D-Phenylglycine from isopropyl D-phenylglycinatehydrochloride Isopropyl D-phenylglycinate hydrochloride 1 13.96 g.,0.061 moles. [011,3 69 100. H O)! was refluxed in 6N-hydrochlorie acid(30.5 ml.. 0.183 moles. 3 equiv.) for 1 hour (time until refluxing wasminutes). Water 120 ml.) was added, and the solution was cooled in iceand the pH adjusted to 7.0 with 0.880 ammonium hydroxide (25 ml.). TheD-phenylglycine was filtered, washed and dried to give plates (5.70 g.,62% {011 154.5 c 1.013,lN-HC1), [04],, 155.5 (c 1.0,lN-l-1Cl), Thefiltrate (218 ml.) and washings (45 ml.) had rotations of 1 .45 and 0.54respectively in a 1 dm. polarimeter tube.

EXAMPLE l9 D-Phenylglycine from ethyl D-phenylglycinate hydrochloride.

Ethyl D-phenylglycinate hydrochloride (9.77g; 0.043 mole, [01],, 91; wasadded to 6N-hydrochloric acid (21.5 ml., 3 equiv.) which was refluxedfor 1. hour (time until refluxing 8 minutes). Water (100 ml.) was added,the solution was cooled to 0 and the pH adjusted to 7.0 with 0.880ammonium hydroxide (16.6 ml.). The phenylglycine was filtered, washedand dried to give plates (4.18 g., 64 percent), [M -157 (c1.002,1N-HC1).

EXAMPLE Racemisation of methyl L-phenylglycinate(+)-hemitartrate withsodium hydroxide in dry methanol.

EXAMPLE 21 Racemisation of methyl L-phenylglycinate a. Use of sodiummethoxide A solution of optically impure methyl L- phenylglycinate(+)-hemitartrate (2.67 g., the filtrate from a resolution analogous tothat of Example 9, [01],,

+64, containing 0.25 mole excess of tartaric acid) in water (10 ml.) wasneutralised to pH 7.0 with ammonium hydroxide (2.0 ml.) and extractedwith ethyl acetate. The organic layer was washed. dried, and evaporatedto give the crude L-methyl ester (0.741 g., 67 percent) [02],, +102 (c1.02, (1N HCl). The ester was about 75 percent optically pure. Esterprepared in this way (11.2 g.) had a rotation ot'+88.5 in at 10cm.polarimeter tube. Sodium methoxide in dry methanol 10 percent NaOMe in lml. methanol) was added and the rotation of the product was found to beH).95 after 2 hours. The solution was filtered 100 mg. solid), washedwith water and extracted into ethyl acetate which was dried andevaporated to give the DL-ester (6.8 g. 61 percent). identical to anauthentic sample.

b. Use of aqueous acetic acid.

A solution of methyl L-phenylglycinate 1.05 g.) was refluxed in aceticacid containing 10 percent water (20 ml.) for 1 hour. The rotation ofthe solution (measured in a 2.5 cm. polarimeter tube) dropped from 4.3to 0. 1. The solution was cooled and filtered to give a solid (0.262 g.;[a],,' -0.7 (c 1.00, lN-HCI) DL- phenylglycine, 27 percent) and afiltrate which was neutralised with sodium bicarbonate and extractedinto ethyl acetate. The organic layer was washed. dried. and evaporatedto give the DL-ester as an oil (0.383 g.. 36.5 percent), [01],, +3.5 (c1.04, lN-HCl).

c. Use of dry acetic acid.

A solution of methyl L-phenylglycinate (1.11 g.) in glacial acetic acid(made up to 10 ml.) had a rotation of +7.4 in a 5 cm. polarimeter tube.The solution was refluxed for 5 minutes and cooled. The rotation was+O.2 in a 5 cm. polarimeter tube, which corresponds to 97 percentracemisation.

EXAMPLE 22 Racemisation of methyl L-phenylglycinate (+)-hemitartrate a.1n methanol The filtrate from Example 9 was evaporated to give the(+)-hemitartrate of methyl L-phenylglycinate 18.0 g., percent, [04],,+64 (c 1.00, H O). A solution of this material (2.0 g.) in methanol (20ml.) was refluxed for 8 hours, by which time the specific rotation haddropped to +15", which corresponds to 95 percent racemisation.

b. 1n l.M.S. containing 10 percent water A solution of methylL-phenylglycinate (+)-hemitartrate 10.5 g., [01],, +64) in lMScontaining 10 percent water and refluxed for 5 hours. The specificrotation dropped to 13.5 (probably mainly the contribution of tartaricacid). A solid (1.036 g., phenylglycine, [01],, +10, 21 percent) wasprecipitated during the reaction.

The racemised tartrate contained some ethyl ester hemitartrate.

EXAMPLE 23 Resolution of pure methyl-DL-phenylglycinate with tartaricacid in methanol/1,2-dich1oroethane To a solution of L(+)tartaric acid(1.0 g: 0.0067 mole) in methanol/1.2-dichloroethane (30 ml: 2/1) kept atabout 50C was added pure methyl-DL- phenylglycinate (1.0 g: 0.0061mole).

The solution was allowed to cool to 5C and was then allowed to stand atthat temperature for 16 hours. The hemitartrate crystals were filteredoffiwashed with a solution of methanol/1.Z-dichloroethane and then driedunder vacuum at 40C to yield methyl D()- phenylglycinate (+)hemitartrate(0.38 g: 40 percent) 1011f" 63.2 (H O).

EXAMPLE 24 Recrystallisation of the methyl D-phenylglycinatehemitartrate The title hemitartrate (40.0g.) with specific rotation of62 was recrystallised from hot 1.M.S. containing 10 percent water (500ml.) to give needles (31.3 g: 78 percent), [01],, 64 (C 1.0, H 0). Therecrystallised sample was again recrystallised to give needles (81 per-I HCl),

centyield), m.p. 141-143, 011,9 64(C 0.94, H20),

11 (nujol) 3480, 3410 (OH), 2650 (NH;,*), 1740 and 1250 (CO R), 736 and690 cm (Ph), 1' (D 60 MHz) 2.7 proton singlet; Ph), 4.7 l protonsinglet; CH-Ph). 5.5 (2 proton singlet; [CHOH]- 6.2 3 proton singlet; COMe). (Found: C, 47.75; H, 5.2; N, 4.0, C, H NO,,. 0.5 H 0 requires C.47.86; H, 5.5; N, 4.3 percent).

EXAMPLE 25 EXAMPLE 26 Ethyl D-phenylglycinate A solution of ethylD-phenylglycinate (+)--hemitartrate (385 mg., 1.17 mmole, [04],, 48.5)in water (5 ml.) was treated with saturated sodium bicarbonate solution(4.0 ml.) and extracted into ethyl acetate. The organic layer waswashed, dried, and evaporated to give the title ester as a yellow oil(0.215 g., 100 percent), [152] 116 (c 1.00. MeOH), u (CHBr 3340 and 3400(NH-2), 1725 (CO R). r (CDCl 2.65 (5H, s', Ph), 5.40 (1 H. bs; CH), 5.83(2 H. q, .1 7 Hz; Et), 8.0 (2 H, bs; NH 8.81 (3 Hot, .1 7 Hz; Et)(Found: C, 65.0; H, 7.1; N, 8.3. C H NO requires C, 67.0; H, 7.1; N, 7.8percent R 0.4 (Merck plate developed by CHCl :acetone=4:1, purple colourwith ninhydrin spray).

EXAMPLE 27 Methyl D-phenylglycinate A solution of methylD-phenylglycinate (+)-hemitartrate (2.07 g., 6.6 mmole. (all, 64") inwater (12 ml.) was neutralised to pH 7.0 with sodium bicarbonate andextracted with ethyl acetate. The organic layer was washed, dried andevaporated to give an oil which crystallised on cooling to give thetitle D-ester (0.63 g., 58 percent) m.p. 29 to 32, [01],, 139 (0 1.023,IN-

V (CHBTg) 3400 and 3330 (NH 1722 cm. (CO R), 'r (CDCl 2.65 (5 H, s; Ph).4.38 (1 H, s; CH), 6.3 (3 H, s; Me). 8.1 (2 H, s; NH (Found: C, 65.4; H.6.6; N, 8.7. C H NO requires C, 65.4; H. 6.7".

N, 8.5 percent), R, 0.4 (Merck plate developed by chloroformzacetone=4zl. purple colour with ninhydrin spray).

EXAMPLE 28 Methyl D-phenylglyeinate hydrochloride A solution of methylD-phenylglycinatc (+)-hemitartrate (2.02 g., 6.4 mmole. [0111) 64 fromExample 24) in water ml.) was stirred with calcium chloride dihytlratc(0.942 g., 6.4 mmole, 1 equiv.) in water (5 ml.). After 2 hours calciumtartrate was filtered off (0.79 g.. 66 percent), and the filtrate wasevaporated to dryness to give the hydrochloride as a white powder (2.190g., 170 percent, but hydrated, and containing inorganic material) [01],,64(c 1.00, H O).

EXAMPLE 29 Ethyl D-phenylglycinate hydrochloride Ethyl D-phenylglycinatehemitartrate 1.149 g., [01],, 46"), made as in Example 8(a), in water (5ml.) was neutralised to pH 7.0 and extracted with ethyl acetate. Theorganic layer was washed with water then extracted into 2N-hydrochloricacid. The acid layer was evaporated to dryness to give the hydrochloride(0.712 g., 95 percent), [011 85.5 (c 1.01, H O).

EXAMPLE 30 Resolution of methyl DL-phenylglycinate in methanolcontaining dichloroethane A solution of methyl DL-phenylglycinate (970mg., 5.9 mmole) and (+)-tartaric acid (980 mg 6.5 mmole 1.1 equiv.) wasdissolved in methanolzdichloroethane (1:1; 5 ml.) and seeded with a puresample of the hemitartrate. After 29 hours at 20 to 25 the solid wasfiltered, washed, and dried at to /2mm for 2 hours to give thehemitartrate (0.454 g., 49 percent) [04],, 61.5 (c 1.00, H O).

EXAMPLE 31 Resolution of methyl DL-phenylglycinate in ethanol containingdimethylsulphoxide A solution of methyl DL-phenylglycinate (2.02 g.,12.2 mmole) and (+)-tartaric acid (1.91 g., 12.8 mmole, 1.05 equiv.) inethanol containing 9 percent v/v dimethylsulphoxide (45 ml.) was seededwith optically pure methyl D-phenylglycinate (+)-hemitartrate. Thesolution crystallised at28 was cooled to 4,filtered, washed, and driedat 70 to 80l2mm to give the hemitartrate (1.56 g., percent), [04],, 6l(c 1.00 H O).

EXAMPLE 32 Resolution of methyl DL-phenylglycinate in ethanol containingacetic acid A solution of methyl DL-phenylglycinate (2.00 g., 12.1mmole) and (+)-tartaric acid (1.89 g 12.7 mmole, 1.05 equiv.) in ethanolcontaining 9 percent v/v acetic acid (45 ml.) was seeded with opticallypure methyl D- phenylglycinate (+)-hemitartrate. The solutioncrystallised immediately at 28, and was cooled to 4, filtered, washed,and dried at 70 to 80l2mm to give the hemitartrate (1.585 g., 85percent), [01],, 59 (c EXAMPLE 33 Resolution of ethyl DL-phenylglycinatein 10 percent aqueous ethanol Ethyl DL-phenylglycinate (4.00 g., 22.4mmole) and (+)-tartaric acid were dissolved in 10 percent aqueousethanol (90 ml.) at 50. cooled and seeded with optically purehemitartrate. After 20 hours at 20 the fine needles were filtered.washed, and dried at 20/1mm for 3 hours to give the hemitartrate (1.46g., 38 percent), [a],, 48 (c 3.13, H O).

The filtrate was cooled to 3 to give a second crop (1.10 g., 27percent), [01],, 50 (c 2.8, H This fil trate was cooled to 27 to give athird crop (310 mg., 7.5 percent), [al -41 (c 2.1, H 0).

EXAMPLE 34 Resolution of ethyl DL-phenylglycinate in 7.5 percent aqueousethanol A solution of ethyl DL-phenylglycinate (5.15 g., 28.8

mmole) and (+)-tartaric acid (4.85 g., 32 mmole, 1.1 7

EXAMPLE 35 Resolution of ethyl DL-phenylglycinate in ethanol containingA. percent Acetic Acid A solution of ethyl DL-phenylglycinate (950 mg.,5.4 mmole) and (+)-tartaric acid (939 mg., 6.2 mmole, 1.18 equiv.) inethanol containing 5 percent acetic acid (19 m1) at 60 was cooled andseeded. It was crystallised at 4, filtered, washed, and dried at 70/2mmto give the hemitartrate (709 mg, 80 percent), [a],, 36 (c 2.5 H 0). Thefiltrate was racemised by keep ing it at 40 for 4 days. It was cooled to4 to give a second crop (273 mg., 31 percent), [a],, -46 (c 2.40, H O).

B. percent Acetic acid As in Example A, but using 10 percent v/v aceticacid and a 5 percent solution of the ester to give the hemitartrate (63percent). [a],, 42.5 (c 2.5, H 0) and similarly a second crop (21percent), [odd-' 48 (c 2.0, H 0).

C. percent Acetic acid As in Example A. but using 15 percent \-/1'acetic acid and a 15 percent solution of the ester, to give thehemitartrate (81 percent), [01],, 33 (c 2.4, H 0) and a second crop (13percent), [01],, 38 (c 2.4, H 0).

EXAMPLE 36 Resolution of ethyl DL-phenylglycinate in ethanol containing10 percent dimcthylsulphoxide A solution of ethyl DL-phenylglycinate(900 mg., 5 mmole) and (+)-tartaric acid (900 mg, 6 mmole, 1.2 equiv.)in ethanol containing 10 percent v/v dimethylsulphoxide (12.5 ml) at 50was cooled and seeded. The mixture was crystallized at 4. then filtered.washed, and dried at /2mm to give the hemitartrate (560 mg., 64percent), [01],, 43 (c 1.00, H O).

EXAMPLE 37 Resolution and Racemisation of ethyl DL-phenylglycinate inethanol with 10 percent dimethylsulphoxide A mixture of ethylDL-phenylglycinate (4.85 g., 27.1 mmole) and (+)-tartaric acid (4.065g., 27.1 mmole, 1 equiv.) was stirred in ethanol containing 10 percentdimethylsuiphoxide (50 ml. crystallisation had occurred after 10minutes. The mixture was stirred at 20 for 10 days to give thehemitartrate (4.886 g., 96 percent), [a),, 46.8 (c 2.504, water).

The filtrate was concentrated to 21 ml then racemised by keeping it at40 for 8 days. Ethanol (29 ml.) was added and the solution wascrystallised at 4 to give a second crop (1.739 g., 34 percent), [11],,45.5 (c 2.483, water).

EXAMPLE 38 Resolution and racemisation of ethyl DL-phenylglycinate inethanol containing 10 percent acetic acid 7 A solution of ethylDL-phenylglycinate (3.62 20.3 mmole) and (+)-tartaric acid (3.05 g.,20.4 mmole, 1 equiv.) in ethanol containing 10 percent v/v acetic acid(38 ml.) was stirred at 20. After 5 minutes crystallisation began. Themixture was filtered after 12 days, washed and dried at 20/2 mm. to givethe hemitartrate (4.157 g., 109 percent) [a],, 42.5 (c 2.99, H O).

The filtrate was racemised by heating at 40 for 4 days. It was stirredat 20 for 3 days then at 4 for 3 days, filtered washed and dried at20/3mm to give a second crop of the hemitartrate (0.71 l g., 19percent), [01],, 41.8 (c 2.497, 11 0).

EXAMPLE 39 Racemisation of methyl and ethyl L-phenylglycinate(+)-hemitartrates The results are summarised in Tables 2 and 3. Thefollowing is a typical procedure.

A solution of the L-hemitartrate (often the filtrate from a resolution)in the stated solvent was kept at various temperatures. The rotation ofthe solution was measured at intervals. The time for the rotation tofall to a point half-way between the initial rotation and the racemicvalue was noted and is shown in Tables 2 and TABLE 2 Racemisation ofmethyl L-phenylglycinatc hemitartrate in ethanol and methanol andshowing the effect of polar and non-polar additives Sohent hemitartrate'l'cmpcrature Conditions Time for 5( 1' raccmisation Ethanol EthanolEthanol Ethanol Methanol TABLE 2 Continued Racemisation of methylL-phenylglycinate hemitartrate In ethanol and methanol and showing theeffect of polar and non-polar additives Time for 50% No. Solventhemitartrate Temperature Conditions racemisation 6 Methanol S 60 20% v/vacetonitrile 5.6 hours 7 Methanol 5 60 3.9 hours 8 Methanol l Reflux 2.8hours TABLE 3 Racemisation of ethyl L-phenylglycinate hernitartrate inethanol Time for 50% No hemitartrate Temperature Conditions racemisationl 20-25 v/v DMSO 100 hours 2 5 -25 1 L6 moles acetic acid (10%) 100hours 3 1 40 50 hours 4 5 40 1 L6 moles acetic acid 21.2 hours 5 5 40l0% v/v DMSO 20 hours 6 1 50 hours 7 2 50 1 mole tartaric acid 2l.4hours 8 2 50 5 moles tartaric acid 21.4 hours 9 2 50 1 mole acetic acid9.2 hours l0 2 50 5 moles acetic acid 6.9 hours I l 2 50 10 moles aceticacid 5.2 hours 12 1 65 7.9 hours 13 l 80 2.5 hours EXAMPLE 40 vents,amide solvents, ester solvents, carboxylic acid Resolution of puremethyl-DL-phenylglycinate with tartaric acid in methanol/methylenechloride To a solution of (+)tartaric acid 1.0 g: 0.0067 mole) inmethanol/methylene chloride (30 mls: /2) kept at a temperature of about5 0C was added pure methyl-DL- phenylglycinate (+)-hemitartrate (1.0 g:0.0061 mole). The solution was allowed to cool to 5C and was thenallowed to stand at that temperature for 16 hours. The hemitartratecrystals were filtered off, washed with a solution of methanol/methylenechloride and then dried under vacuum at C to yield D(+)phenylglycinemethyl ester (+)hemitartrate (0.71 g:74 percent yield) 01 59.9 (H O).

What is claimed is:

1. A process for the resolution ofa DL-phenylglycine ester of theformula:

where R represents an alkyl group with 1 to 6 carbon atoms or acycloalkyl group withh 5 or 6 carbon atoms, which comprises treatingsaid DL-phenylglycine ester with (+)-tartaric acid at a temperature offrom 15 to 60C in the presence of a mixture of solvents of differentpolarities one of which is an alkanol having l-4 carbon atoms, the said(+)-tartaric acid being used in a stoichiometric amount or in an excessup to 100 percent, and selectively crystallising the (+)-hemitartrate ofthe D-phenylglycine ester therefrom at a temperature of from 20 to +60C.

2. A process as claimed in claim 1 wherein a DL- P nylglycine ester isused in which R represents a yl. ethyl. isopropyl, butyl. isobutyl orcyclohexyl group.

3. A process as claimed in claim 1 wherein said mixture of solventscontains a solvent selected from among the following: water, sulphoxidesolvents, nitrile solsolvents and hydrocarbon and chlorinatedhydrocarbon solvents.

4. A process as claimed in claim 1 wherein the alkanol is methanol.

5. A process as claimed in claim 1 wherein the alkanol is ethanol.

6. A process as claimed in claim 1 wherein said mixture of solventscontains water.

7. A process as claimed in claim 3 wherein said sulphoxide solventcomprises dimethylsulphoxide.

8. A process as claimed in claim 1 for the resolution of ethylDL-phenylglycinate wherein the resolution is effected in the presence ofaqueous methanol or aqueous ethanol as solvent.

9. A process as claimed in claim 1 for the resolution of methylDL-phenylglycinate wherein the resolution is effected in the presence ofaqueous ethanol or aqueous industrial methylated spirit (I.M.S.) assolvent.

10. A process as claimed in claim 1 wherein the (+)-hemitartrate of theD-phenylglycine ester thus obtained is hydrolysed in an aqueous solutionof a strong acid, whereby a salt of D-phenylglycine is obtained.

11. A process as claimed in claim 10 wherein the pH of the hydrolysismixture, containing the salt of D- phenylglycine thus formed, isadjusted to the range 4-9 whereby D-phenylglycine is obtained.

12. A process for the resolution of a DL- phenylglycine ester of theformula where R represents an alkyl group with l to 6 carbon atoms or acycloalkyl group with 5 or 6 carbon atoms, which comprises theresolution steps of treating said DL-phenylglycine ester with(+)-tartaric acid at a temperature of from 15 to 60C in the presence ofa mixture of solvents of different polarities one of which is an alkanolhaving 1 to 4 carbon atoms, the said (+)-tartaric acid being used in astoichiometric amount or in an excess up to 100 percent, and selectivelycrystallising the (+)-hemitartrate of the D-phenylglycine estertherefrom at a temperature of from to +60C; separating said crystallized(+)-hemitartrate from the remaining L-phenylglycine ester or saltthereof, racemising said remaining L-phenylglycine ester or salt thereofand resolving said racemate by repeating said resolution steps.

13. A process as claimed in claim 12 in which racemisation is effectedby heating the L-phenylglycine ester or salt alone or in solution,either in the solvent mixture used for resolution or in a differentsolvent medium.

14. A process as claimed in claim 13 in which, in order to racemise anyL-phenylglycine ester, a base or a weak acid is added to the solution.

15. A process as claimed in claim 12 in which said racemisation takesplace simultaneously with resolution.

16. A compound of the general formula:

CHCH COR wherein A represents the (+)-hemitartrate anion and Rrepresents an alkyl group with 1 to 6 carbon atoms or a cycloalkyl groupwith 5 or 6 carbon atoms in substantially optically pure form.

17. A compound as claimed in claim 16 selectedfrom the group consistingof D-phenylglycine methyl ester (+)-hemitartrate in substantiallyoptically pure form; D-phenylglycine ethyl ester (+)-hemitartrate in substantially optically pure form; and D-phenylglycine isopropyl ester(+)-hemitartrate in substantially optically pure form. 18.D-phenylglycine methyl ester in substantially optically pure form; or

D-phenylglycine ethyl ester in substantially optically pure form.

1. A process for the resolution of a DL-phenylglycine ester of theformula: C6H5CH.NH2.CO2R where R represents an alkyl group with 1 to 6carbon atoms or a cycloalkyl group withh 5 or 6 carbon atoms, whichcomprises treating said DL-phenylglycine ester with (+)-tartaric acid ata temperature of from 15* to 60*C in the presence of a mixture ofsolvents of different polarities one of which is an alkanol having 1-4carbon atoms, the said (+)-tartaric acid being used in a stoichiometricamount or in an excess up to 100 percent, and selectively crystallisingthe (+)-hemitartrate of the D-phenylglycine ester therefrom at atemperature of from -20* to +60*C.
 1. A PROCESS FOR THE RESOLUTION OF ADL-PHENYLGLYCINE ESTER OF THE FORMULA:
 2. A process as claimed in claim1 wherein a DL-phenylglycine ester is used in which R represents amethyl, ethyl, isopropyl, butyl, isobutyl or cyclohexyl group.
 3. Aprocess as claimed in claim 1 wherein said mixture of solvents containsa solvent selected from among the following: water, sulphoxide solvents,nitrile solvents, amide solvents, ester solvents, carboxylic acidsolvents and hydrocarbon and chlorinated hydrocarbon solvents.
 4. Aprocess as claimed in claim 1 wherein the alkanol is methanol.
 5. Aprocess as claimed in claim 1 wherein the alkanol is ethanol.
 6. Aprocess as claimed in claim 1 wherein said mixture of solvents containswater.
 7. A process as claimed in claim 3 wherein said sulphoxidesolvent comprises dimethylsulphoxide.
 8. A process as claimed in claim 1for the resolution of ethyl DL-phenylglycinate wherein the resolution iseffected in the presence of aqueous methanol or aqueous ethanol assolvent.
 9. A process as claimed in claim 1 for the resolution of methylDL-phenylglycinate wherein the resolution is effected in the presence ofaqueous ethanol or aqueous industrial methylated spirit (I.M.S.) assolvent.
 10. A process as claimed in claim 1 wherein the(+)-hemitartrate of the D-phenylglycine ester thus obtained ishydrolysed in an aqueous solution of a strong acid, whereby a salt ofD-phenylglycine is obtained.
 11. A process as claimed in claim 10wherein the pH of the hydrolysis mixture, containing the salt ofD-phenylglycine thus formed, is Adjusted to the range 4-9 wherebyD-phenylglycine is obtained.
 12. A process for the resolution of aDL-phenylglycine ester of the formula C6H5CH.NH2.CO2R where R representsan alkyl group with 1 to 6 carbon atoms or a cycloalkyl group with 5 or6 carbon atoms, which comprises the resolution steps of treating saidDL-phenylglycine ester with (+)-tartaric acid at a temperature of from15* to 60*C in the presence of a mixture of solvents of differentpolarities one of which is an alkanol having 1 to 4 carbon atoms, thesaid (+)-tartaric acid being used in a stoichiometric amount or in anexcess up to 100 percent, and selectively crystallising the(+)-hemitartrate of the D-phenylglycine ester therefrom at a temperatureof from -20* to +60*C; separating said crystallized (+)-hemitartratefrom the remaining L-phenylglycine ester or salt thereof, racemisingsaid remaining L-phenylglycine ester or salt thereof and resolving saidracemate by repeating said resolution steps.
 13. A process as claimed inclaim 12 in which racemisation is effected by heating theL-phenylglycine ester or salt alone or in solution, either in thesolvent mixture used for resolution or in a different solvent medium.14. A process as claimed in claim 13 in which, in order to racemise anyL-phenylglycine ester, a base or a weak acid is added to the solution.15. A process as claimed in claim 12 in which said racemisation takesplace simultaneously with resolution.
 16. A compound of the generalformula:
 17. A compound as claimed in claim 16 selected from the groupconsisting of D-phenylglycine methyl ester (+)-hemitartrate insubstantially optically pure form; D-phenylglycine ethyl ester(+)-hemitartrate in substantially optically pure form; andD-phenylglycine isopropyl ester (+)-hemitartrate in substantiallyoptically pure form.